Risk Stratification of Organ Confined Bladder Cancer After Radical Cystectomy Using Cell Cycle Related Biomarkers

Purpose: We tested whether assessing the expression of cell cycle related proteins (p53, pRB, p21 and p27) could predict clinical outcomes after radical cystectomy in patients with organ confined urothelial carcinoma of the bladder. Materials and Methods: Our study included a development cohort of 272 patients and an external testing cohort of 52 patients with chemotherapy naive pT1-2N0M0 urothelial carcinoma of the bladder treated with radical cystectomy. Immunohistochemical staining of p53, p27, p21 and pRB was performed on the development cohort of 272 patients and the external testing cohort of 52 patients. Results: Overall 260 (80.2%) patients had altered expression of at least 1 molecular marker and 105 (32.4%), 95 (29.3%), 44 (13.6%) and 16 (4.9%) had 1 to 4 altered molecular markers, respectively. Addition of the number of altered molecular markers increased the predictive accuracy of the base model for disease recurrence and cancer specific mortality by 15.6% and 14.8%, respectively (p < 0.001). The base model included age, gender, pT1 vs pT2 stage, grade, number of lymph nodes removed, lymphovascular invasion and concomitant carcinoma in situ. The combination of molecular markers yielded a predictive accuracy superior to that of any single molecular marker. We developed nomograms for the prediction of recurrence-free and cancer specific survival. Conclusions: Assessment of the number of altered cell cycle regulatory proteins in the cystectomy specimen improves the prediction of urothelial carcinoma of the bladder recurrence and survival in patients with organ confined disease. A combination of multiple markers is needed to capture the complex biological behavior of urothelial carcinoma of the bladder.